Cerdulatinib for treating myeloma

ABSTRACT

Compositions and methods for treating multiple myeloma (MM), acute myeloid lymphoma (AML) or a myeloproliferative disease (MPD) in a human patient in need thereof. The methods entail administering to the patient an effective amount of cerdulatinib.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/235,972, filed Aug. 12, 2016, which claims priority to and thebenefit under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationSer. No. 62/204,400, filed on Aug. 12, 2015, and U.S. Provisional PatentApplication Ser. No. 62/342,711, filed on May 27, 2016, the entiredisclosure of each of which is hereby incorporated by reference.

BACKGROUND

Multiple myeloma (MM) is a cancer of plasma cells, a type of white bloodcell normally responsible for producing antibodies. In multiple myeloma,collections of abnormal plasma cells accumulate in the bone marrow,where they interfere with the production of normal blood cells. Mostcases of multiple myeloma also feature the production of a paraprotein,an abnormal antibody which can cause kidney problems. Bone lesions andhypercalcemia (high blood calcium levels) are also often encountered.

Multiple myeloma is diagnosed with blood tests (serum proteinelectrophoresis, serum free kappa/lambda light chain assay), bone marrowexamination, urine protein electrophoresis, and X-rays of commonlyinvolved bones. Multiple myeloma is considered to be incurable buttreatable. Remission may be induced with steroids, chemotherapy,proteasome inhibitors, immunomodulatory drugs such as thalidomide orlenalidomide, and stem cell transplants. Radiation therapy is sometimesused to reduce pain from bone lesions.

Patients with multiple myeloma have an abnormally large number ofidentical plasma cells, and they also have too much of one type ofantibody. The tumor, its products, and the host response to it result ina number of organ dysfunctions and symptoms of bone pain or fracture,renal failure, susceptibility to infection, anemia, hypercalcemia, andoccasionally clotting abnormalities, neurologic symptoms, and vascularmanifestations of hyperviscosity.

Multiple myeloma develops in 6.1 per 100,000 people per year. It is morecommon in men and is twice as common in African Americans as it is inWhite Americans. With conventional treatment, median survival is 3-4years, which may be extended to 5-7 years or longer with advancedtreatments. Multiple myeloma is the second most common hematologicalmalignancy in the U.S. (after non-Hodgkin lymphoma), and constitutes 1%of all cancers. The five year survival rate is 45%.

Two relatively new classes of anti-cancer agents for multiple myelomaare being developed, thalidomide (including the immunomodulatoryderivatives such as lenalidomide) and the proteasome inhibitorsincluding bortezomib. A significant proportion of multiple myelomapatients are resistant to those agents, and initial responders (eventhose achieving durable complete remissions) can eventually relapse.

Acute myeloid leukemia (AML), also known as acute myelogenous leukemiaor acute nonlymphocytic leukemia (ANLL), is a cancer of the myeloid lineof blood cells, characterized by the rapid growth of abnormal whiteblood cells that accumulate in the bone marrow and interfere with theproduction of normal blood cells. AML is the most common acute leukemiaaffecting adults, and its incidence increases with age. Although AML isa relatively rare disease, accounting for roughly 1.2% of cancer deathsin the United States, its incidence is expected to increase as thepopulation ages. The myeloproliferative neoplasms (MPNs), ormyeloproliferative diseases (MPDs), are a group of diseases of the bonemarrow in which excess cells are produced. They are related to, and mayevolve into, myelodysplastic syndrome and acute myeloid leukemia.

The development of more efficacious therapies for MM, AML and MPD isurgently needed.

SUMMARY

The present examples demonstrate that cerdulatinib dose-dependentlyactivated apoptosis and inhibit cell proliferation of various multiplemyeloma (MM) cell lines. Further, such activity of cerdulatinib isindependent of FGFR3. Moreover, the anti-cancer activity of cerdulatinibwas also demonstrated in other myeloma cancer cells including those ofacute myeloid lymphoma (AML) and myeloproliferative diseases (MPD).Therefore, the experimental data presented here show that cerdulatinibis an efficacious anti-cancer agent for various myelomas and plasma celldisorders.

Cerdulatinib is a small molecule, ATP-competitive, reversible inhibitorof both SYK and JAK family members and is described in U.S. Pat. No.8,138,339. Cerdulatinib has a chemical name of4-(cyclopropylamino)-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenylamino)pyrimidine-5-carboxamide,and the structure of formula I:

In one embodiment, the present disclosure provides a method of treatingmultiple myeloma (MM), acute myeloid lymphoma (AML) or amyeloproliferative disease (MPD) in a human patient in need thereof,comprising administering to the patient an effective amount ofcerdulatinib or a pharmaceutically acceptable salt thereof. Theeffective amount can be from about 5 mg to about 150 mg daily.

In some embodiments, the patient is not being treated with fludarabine.In some embodiments, the patient is not being treated with a purineanalog. In some embodiments, the patient is not being treated with anagent that interferes with DNA synthesis.

The administration may be once daily or twice daily. When administeredtwice daily, the effective amount may be from about 25 mg to about 65 mgtwice daily, or more specifically about 30 mg, 35 mg, 40 mg, 45 mg, or50 mg twice daily.

In some embodiments, the patient suffers from an advanced malignancy ofMM, AML or MPD. In some embodiments, the patient has relapsed or notresponded to a prior chemotherapy. In some embodiments, the patient hasfailed at least two prior therapies. In some embodiments, the multiplemyeloma is a Stage I, Stage II, or Stage III multiple myeloma.

In some embodiments, the patient has an albumin level lower than 3.5mg/dL. In some embodiments, the patient has a B2-microglobulin levelfrom 3.5 to 5 mg/L or greater than 5 mg/L. In some embodiments, thepatient has an FGFR3 activation mutation.

Non-limiting examples of multiple myeloma include Monoclonal Gammopathyof Undetermined Significance (MGUS), Asymptomatic (Smoldering/Indolent)Myeloma, or Symptomatic (Active) Myeloma.

In some embodiments, the method further comprises administering to thepatient a second agent, which may be a P90RSK inhibitor or selected fromthe group consisting of dexamethasone, melphalan, doxorubicin,bortezomib, lenalidomide, prednisone, carmustine, etoposide, cisplatin,vincristine, cyclophosphamide, BI-D1870, and thalidomide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents gel pictures showing basal p90RSK expression in variousmultiple myeloma cell lines. The expression levels of phospho-p90RSK orRSK-5380 were not associated with FGFR3 expression.

FIG. 2 is a chart showing that, in both FGFR3 positive and FGFR3negative multiple myeloma cell lines, p90RSK inhibitor BI-D1870dose-dependently activated caspase3 expression, an indication of inducedapoptosis.

FIG. 3 is a chart showing that, in both FGFR3 positive and FGFR3negative multiple myeloma cell lines, p90RSK inhibitor BI-D1870dose-dependently inhibited cell proliferation (EdU as indicator).

FIG. 4 is a chart showing that, like BI-D1870, cerdulatinib (Cerd)dose-dependently activated caspase3 expression, an indication of inducedapoptosis, in both FGFR3 positive and FGFR3 negative multiple myelomacell lines. Also, there was no relationship between FGFR3 expression andthe sensitivity to cerdulatinib of the cell lines.

FIG. 5 is a chart showing that, like BI-D1870, cerdulatinib (Cerd)dose-dependently inhibited cell proliferation (EdU as indicator) in bothFGFR3 positive and FGFR3 negative multiple myeloma cell lines. Also,there was no relationship between FGFR3 expression and the sensitivityto cerdulatinib of the cell lines.

FIG. 6 is a chart showing that cerdulatinib was active in killing AMLcells.

FIG. 7 compares the IC₅₀ of cerdulatinib to Comp A, a Syk inhibitor,across cancer types.

DETAILED DESCRIPTION

It is to be understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

1. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. As used herein the followingterms have the following meanings.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “anagent” includes a plurality of agents.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions and methods include the recited elements, but notexcluding others. “Consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition consisting essentially of the elements as defined hereinwould not exclude other materials or steps that do not materially affectthe basic and novel characteristic(s) claimed. “Consisting of” shallmean excluding more than trace elements of other ingredients andsubstantial method steps. Embodiments defined by each of thesetransition terms are within the scope of this disclosure.

The term “about” when used before a numerical designation, e.g.,temperature, time, amount, and concentration, including range, indicatesapproximations which may vary by (+) or (−) 10%, 5% or 1%.

As used herein, the term “treating and/or preventing” refers topreventing, curing, reversing, attenuating, alleviating, minimizing,suppressing or halting tumor growth, spreading, metastasis, ordevelopment.

As used herein, the term “patient” refers to a subject having a canceror tumor, which can be benign or malignant. In certain embodiments, thepatent is a human or an animal.

As used herein, the term “pharmaceutically acceptable” indicates thatthe indicated material does not have properties that would cause areasonably prudent medical practitioner to avoid administration of thematerial to a patient, taking into consideration the disease orconditions to be treated and the respective route of administration. Forexample, it is commonly required that such a material be essentiallysterile.

As used herein, the term “pharmaceutically acceptable carrier” refers topharmaceutically acceptable materials, compositions or vehicles, such asa liquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting any supplement orcomposition, or component thereof, from one organ, or portion of thebody, to another organ, or portion of the body, or to deliver an agentto the cancerous tissue or a tissue adjacent to the cancerous tissue.

As used herein, the term “formulated” or “formulation” refers to theprocess in which different chemical substances, including one or morepharmaceutically active ingredients, are combined to produce a dosageform. In certain embodiments, two or more pharmaceutically activeingredients can be co-formulated into a single dosage form or combineddosage unit, or formulated separately and subsequently combined into acombined dosage unit. A sustained release formulation is a formulationwhich is designed to slowly release a therapeutic agent in the body overan extended period of time, whereas an immediate release formulation isa formulation which is designed to quickly release a therapeutic agentin the body over a shortened period of time.

As used herein, the term “delivery” refers to approaches, formulations,technologies, and systems for transporting a pharmaceutical compositionin the body as needed to safely achieve its desired therapeutic effect.In some embodiments, an effective amount of the composition isformulated for delivery into the blood stream of a patient.

As used herein, the term “solution” refers to solutions, suspensions,emulsions, drops, ointments, liquid wash, sprays, liposomes which arewell known in the art. In some embodiments, the liquid solution containsan aqueous pH buffering agent which resists changes in pH when smallquantities of acid or base are added.

2. Myeloma Treatments

As shown in the examples, cerdulatinib dose-dependently activatedapoptosis and inhibited cell proliferation of various multiple myeloma(MM) cell lines and had potent cytotoxicity in other myeloma cancercells including those of acute myeloid lymphoma (AML) andmyeloproliferative diseases (MPD). Therefore, the experimental datapresented here show that cerdulatinib is an efficacious anti-canceragent for various myelomas and disorders.

Cerdulatinib is a small molecule, ATP-competitive, reversible inhibitorof both SYK and JAK family members. Cerdulatinib has a chemical name of4-(cyclopropylamino)-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenylamino)pyrimidine-5-carboxamide,and the chemical structure of formula I:

In accordance with one embodiment of the disclosure, provided is amethod of treating a myelomas or a plasma cell disorder, such asmultiple myeloma (MM), acute myeloid lymphoma (AML) and amyeloproliferative disease (MPD). In some aspects, the method comprisesadministering to a human patient in need thereof an effective amount ofcerdulatinib,4-(cyclopropylamino)-2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenylamino)pyrimidine-5-carboxamide,or a pharmaceutically acceptable salt thereof.

In some aspects, the method does not include administration offludarabine (or the patient is not concurrently treated withfludarabine). Fludarabine is a purine analog that interferes with DNAsynthesis. In some aspects, the method does not include administrationof a purine analog (or the patient is not concurrently treated with apurine analog). In some aspects, the method does not includeadministration of an agent that interferes with DNA synthesis (or thepatient is not concurrently treated with an agent that interferes withDNA synthesis).

The data show that cerdulatinib is efficacious in myeloma cellsregardless of FGFR3 status. In one embodiment, therefore, cerdulatinibis administered to a patient that has an FGFR3 mutation, such as thet(11;24) or the t(4;14) translocation mutation (FGFR3 positive). In oneembodiment, cerdulatinib is administered to a patient that has awild-type FGFR3.

It is contemplated that cerdulatinib treatment is applicable to amyeloma patient that is at an advanced stage, or that is resistant(refractory) to other chemotherapeutic drugs, or a myeloma patient thathas been prior-treated with one or more other chemotherapeutic drugs.

It is contemplated that cerdulatinib treatment is applicable to amyeloma patient that falls into any category, subcategory, or stage ofthe diseases, e.g., MM, AML or MPD, such as those described below.

Multiple Myeloma (MM)

Ducie-Salmon Staging

In this system, there are three stages of myeloma: Stage I, Stage II,and Stage III. The stage depends on factors including:

-   -   The amount of myeloma cells in the body    -   The amount of damage the myeloma cells have caused to the bone    -   Levels of M-protein in the blood or urine    -   Blood calcium levels    -   Albumin and hemoglobin levels

Myeloma can also be further classified into Group A or Group B, based ondamage to the kidneys. Group A indicates normal kidney function whileGroup B indicates abnormal kidney function. A person could beclassified, for example, as Stage IIB.

International Staging System (ISS)

This staging system is based on the albumin level (more or less than 3.5mg/dL) and B2-microglobulin level (<3.5; 3.5-5 or >5 mg/L). The higherthe stage, the poorer the outcome. This staging system is based onoutcomes of more than 10,000 cancer patients?.

Types

There are different forms of myeloma-related conditions as detailedbelow. Some require treatment, some do not, but all will require regularcheck-ups to monitor whether the disease is progressing.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

People who have MGUS harbor a small number of myeloma cells in the bonemarrow but these cells do not form a tumor and symptoms of the myelomaare not present. This condition is usually discovered during a routineblood exam that shows unusual levels of protein in the blood.

MGUS is a pre-cancerous condition. Therefore, check-ups should occurevery six months to monitor the condition and make sure that it does notdevelop into multiple myeloma, even though this only happens in a smallamount of patients.

A diagnosis of MGUS should not be made without having performedchromosome analysis, gene array, MRI, and/or a PET/CT scan.

Asymptomatic (Smoldering/Indolent) Myeloma

Asymptomatic myeloma falls somewhere between MGUS and overt, symptomaticmultiple myeloma. In this condition, a person has a greater number ofmyeloma cells than a person with MGUS. However, the disease does notcause any damage to the body and the typical myeloma symptoms are notpresent, though patients may exhibit anemia due to causes other than themyeloma.

Asymptomatic myeloma can be stable for many months or years, but itultimately tends to progress. Treatment will likely be needed at somepoint. Patients will need to be monitored to see if the diseaseprogresses and if symptoms become evident.

Symptomatic (Active) Myeloma

This type of myeloma represents overt cancer. A person with symptomaticmyeloma has more myeloma cells than a person with asymptomatic myelomaor MGUS.

At this point, the disease is causing damage to the body, like bonedamage, anemia, kidney problems, or hypercalcemia (high levels ofcalcium in the blood).

Acute Myeloid Leukemia (AML)

According to the widely used WHO criteria, the diagnosis of AML isestablished by demonstrating involvement of more than 20% of the bloodand/or bone marrow by leukemic myeloblasts. The French-American-British(FAB) classification requires a blast percentage of at least 30% in bonemarrow (BM) or peripheral blood (PB) for the diagnosis of AML.myeloproliferative syndromes, which are treated differently.

The WHO subtypes of AML include (1) acute myeloid leukemia withrecurrent genetic abnormalities, which include:

-   -   AML with translocations between chromosome 8 and        21—[t(8;21)(q22;q22);] RUNX1/RUNX1T1;    -   AML with inversions in chromosome 16—[inv(16)(p13.1q22)] or        internal translocations in it—[t(16;16)(p13.1;q22);] CBFB/MYH11;        (ICD-O 9871/3);    -   Acute promyelocytic leukemia with translocations between        chromosome 15 and 17—[t(15;17)(q22;q12);] RARA/PML; (ICD-O        9866/3);    -   AML with translocations between chromosome 9 and        11—[t(9;11)(p22;q23);] MLLT3/MLL;    -   AML with translocations between chromosome 6 and        9—[t(6;9)(p23;q34);] DEK/NUP214;    -   AML with inversions in chromosome 3—[inv(3)(q21q26.2)] or        internal translocations in it—[t(3;3)(q21;q26.2);] RPN1/EVI1;    -   Megakaryoblastic AML with translocations between chromosome 1        and 22—[t(1;22)(p13;q13);] RBM15/MKL1;    -   AML with mutated NPM1; and    -   AML with mutated CEBPA;        (2) acute myeloid leukemia with recurrent genetic abnormalities,        which include:    -   AML with complex karyotype    -   Unbalanced abnormalities AML with deletions of chromosome        7—[del(7q);]    -   AML with deletions of chromosome 5—[del(5q);]    -   AML with unbalanced chromosomal aberrations in chromosome        17—[i(17q)/t(17p);]    -   AML with deletions of chromosome 13—[del(13q);]    -   AML with deletions of chromosome 11—[del(11q);]    -   AML with unbalanced chromosomal aberrations in chromosome        12—[del(12p)/t(12p);]    -   AML with deletions of chromosome 9—[del(9q);]    -   AML with aberrations in chromosome X—[idic(X)(q13);]    -   Balanced abnormalities AML with translocations between        chromosome 11 and 16—[t(11;16)(q23;q13.3);], unrelated to        previous chemotherapy or ionizing radiation;    -   AML with translocations between chromosome 3 and        21—[t(3;21)(q26.2;q22.1);], unrelated to previous chemotherapy        or ionizing radiation    -   AML with translocations between chromosome 1 and        3—[t(1;3)(p36.3;q21.1);]    -   AML with translocations between chromosome 2 and        11—[t(2;11)(p21;q23);], unrelated to previous chemotherapy or        ionizing radiation    -   AML with translocations between chromosome 5 and        12—[t(5;12)(q33;p12);]    -   AML with translocations between chromosome 5 and        7—[t(5;7)(q33;q11.2);]    -   AML with translocations between chromosome 5 and        17—[t(5;17)(q33;p13);]    -   AML with translocations between chromosome 5 and        10—[t(5;10)(q33;q21);] and    -   AML with translocations between chromosome 3 and        5—[t(3;5)(q25;q34);]        (3) therapy-related myeloid neoplasms, (4) myeloid sarcoma, (5)        myeloid proliferations related to Down syndrome, (6) blastic        plasmacytoid dendritic cell neoplasm, and (7) AML not otherwise        categorized, such as:    -   AML with minimal differentiation;    -   AML without maturation;    -   AML with maturation;    -   Acute myelomonocytic leukemia;    -   Acute monoblastic and monocytic leukemia;    -   Acute erythroid leukemia;    -   Acute megakaryoblastic leukemia;    -   Acute basophilic leukemia; and    -   Acute panmyelosis with myelofibrosis.

Myeloproliferative Diseases (MPD)

Myeloproliferative diseases include the following classes: (1) chronicmyelogenous leukemia (CML); (2) essential thrombocythemia (ET); (3)polycythemia vera (PV); and (4) primary myelofibrosis (PMF). MPD can bea cellular phase or fibrotic phase.

3. Combination Treatments

In one embodiment, the treatment method can further include achemotherapeutic agent useful for treating the cancer. In anotherembodiment, cerdulatinib is co-administered (simultaneously orsequentially) with a second agent. In one embodiment, the second agentis a chemotherapeutic agent. In one embodiment, the second agent can beselected from one of the classes detailed below.

-   -   Polyfunctional alkylating agents, exemplified by        cyclophosphamide (cytoxan), mechlorethamine, melphalan        (alkeran), chlorambucil (leukeran), thiopeta (thioplex),        busulfan (myleran);    -   Alkylating drugs, exemplified by procarbazine (matulane),        dacarbazine (dtic), altretamine (hexalen), clorambucil,        cisplatin (platinol), carboplatin, ifosafamide, oxaliplatin;    -   Antimetabolites, exemplified by methotrexate (MTX),        6-thiopurines (mercaptopurine [6-mp], thioguanine [6-TG]),        mercaptopurine (purinethol), thioguanine, fludarabine phosphate,        cladribine: (leustatin), pentostatin, flurouracil (5-Fu),        cytarabine (ara-C), azacitidine;    -   Plant alkaloids, terpenoids and topoisomerase inhibitors,        exemplified by vinblastine (velban), vincristine (oncovin),        vindesine, vinorelbine, podophyllotoxins (etoposide (VP-16) and        teniposide (VM-26)), camptothecins (topotecan and irinotecan),        taxanes such as paclitaxel (taxol) and docetaxel (taxotere);    -   Antibiotics, exemplified by doxorubicin (adriamycin, rubex,        doxil), daunorubicin, idarubicin, dactinomycin (cosmegen),        plicamycin (mithramycin), mitomycin: (mutamycin), bleomycin        (blenoxane);    -   Hormonal agents, exemplified by estrogen and androgen inhibitors        (tamoxifen and flutamide), gonadotropin-releasing hormone        agonists (leuprolide and goserelin (Zoladex)), aromatase        inhibitors (aminoglutethimide and anastrozole (arimidex));    -   Miscellaneous Anticancer Drugs, exemplified by amsacrine,        asparaginase (El-spar), hydroxyurea, mitoxantrone (novantrone),        mitotane (lysodren), retinoic acid derivatives, bone marrow        growth factors (sargramostim and filgrastim), amifostine;    -   Agents disrupting folate metabolism, e.g., pemetrexed;    -   DNA hypomethylating agents, e.g., azacitidine, decitabine;    -   Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP)        pathway inhibitors, such as iniparib, olaparib, veliparib;    -   PI3K/Akt/mTOR pathway inhibitors, e.g., everolimus;    -   Histone deacetylase (HDAC) inhibitors, e.g., vorinostat,        entinostat (SNDX-275), mocetinostat (MGCD0103), panobinostat        (LBH589), romidepsin, valproic acid;    -   Cyclin-dependent kinase (CDK) inhibitors, e.g., flavopiridol,        olomoucine, roscovitine, kenpaullone, AG-024322 (Pfizer),        fascaplysin, ryuvidine, purvalanol A, NU2058, BML-259, SU 9516,        PD-0332991, P276-00;    -   Heat shock protein (HSP90) inhibitors, e.g., geldanamycin,        tanespimycin, alvespimycin, radicicol, deguelin, BIIB021;    -   Murine double minute 2 (MDM2) inhibitors, e.g., cis-imidazoline,        benzodiazepinedione, spiro-oxindoles, isoquinolinone, thiophene,        5-deazaflavin, tryptamine;    -   Anaplastic lymphoma kinase (ALK) inhibitors, e.g.,        aminopyridine, diaminopyrimidine, pyridoisoquinoline,        pyrrolopyrazole, indolocarbazole, pyrrolopyrimidine,        dianilinopyrimidine; or    -   Poly [ADPribose] polymerase (PARP) inhibitors, illustrated by        benzamide, phthalazinone, tricyclic indole, benzimidazole,        indazole, pyrrolocarbazole, phthalazinone, or isoindolinone.

In some embodiments, the other chemotherapeutic agent is a p90RSKinhibitor, such as those described in Cohen et al., “A clickableinhibitor reveals context-dependent autoactivation of p90 RSK,” Nat ChemBiol. 2007 March; 3(3): 156-160, and U.S. Pat. No. 7,605,241. In oneaspect, the p90RSK inhibitor is one or more of dexamethasone, melphalan,doxorubicin, bortezomib, lenalidomide, prednisone, carmustine,etoposide, cisplatin, vincristine, cyclophosphamide, BI-D1870, andthalidomide.

4. Administration, Compositions and Dosing

Any effective regimen for administering cerdulatinib may be used. Forexample, the cerdulatinib may be administered as a single dose, oral, asan infusion, or as a multiple-dose daily regimen. The route ofadministration may also depend on the type of cancer. For example, forcancers such as lymphoma or leukemia, the administration may be systemicor oral, whereas a localized delivery may be used for treating a tumor.Further, a staggered regimen, for example, one to five days per week canbe used as an alternative to daily treatment.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundIC₅₀, the biological half-life of the compound, the age, size, andweight of the subject, and the indication being treated. The importanceof these and other factors are well known to those of ordinary skill inthe art. Generally, a dose will be between about 0.01 and 50 mg/kg, or0.1 and 20 mg/kg of the subject being treated. Multiple doses may beused.

In certain embodiments, the therapeutically effective amount ofcerdulatinib used in the methods, either alone or in one of theprescribed combinations, is at least about 10 mg per day. In oneembodiment, the therapeutically effective amount of cerdulatinib is atleast about 10, 20, 30, 40, or 50 mg per dosage. In one embodiment, thetherapeutically effective amount of cerdulatinib is at least about 10,20, 30, 40, 50, 60, 70, 80, 90 or 100 mg per day.

In one embodiment, the therapeutically effective amount of cerdulatinibis from about 10 mg to 150 mg, from about 25 mg to 120 mg, from about 30to 80 mg, from about 40 to 50 mg, or at least 30 mg, 35 mg, 40 mg, 45mg, 50 mg, 55 mg, 60 mg, or 65 mg per day. In one embodiment, thetherapeutically effective amount of cerdulatinib is at least about 15mg, 20 mg, 25 mg, 30 mg, or 35 mg and is administered twice daily.

In certain embodiments, the therapeutically effective amount ofcerdulatinib is no more than about 500, 400, 300, 200, 150, 120, or 100mg per day. In one embodiment, the therapeutically effective amount ofcerdulatinib is no more than about 300, 200, 150, 120, 100, 90, 80, 70,60, 55 or 50 mg per dosage.

In certain embodiments, the therapeutically effective amount ofcerdulatinib is no more than about 100 mg, 95 mg, 90 mg, 85 mg, 80 mg,or 75 mg per day. In certain embodiments, the therapeutically effectiveamount of cerdulatinib is no more than 45 mg, 40 mg, 35 mg, or 30 mg andis administered twice daily.

In one embodiment, the cerdulatinib, whether alone or in combinationwith another agent, is administered at from about 10 mg to 200 mg, fromabout 25 mg to 150 mg, from about 50 to 120 mg, or from about 80 to 100mg a day.

In one embodiment, the therapeutically effective amount of cerdulatinib,whether alone or in combination with another agent, is 25 mg to 120 mgdaily. In some embodiments, the effective amount of cerdulatinib is 25mg to 50 mg twice daily. In certain embodiments, the cerdulatinib,whether alone or in combination with another agent, is administeredonce, twice, three times or four times a day.

In one embodiment, the cerdulatinib, whether alone or in combinationwith another agent, is administered from about 30 mg to about 80 mg oncea day. In one embodiment, the cerdulatinib, whether alone or incombination with another agent, is administered from about 15 mg toabout 40 mg twice a day.

In one embodiment, 45 mg of cerdulatinib, whether alone or incombination with another agent, is administered twice daily. In oneembodiment, 35 mg of cerdulatinib, whether alone or in combination withanother agent, is administered twice daily.

In some embodiments, the effective amount of cerdulatinib, or apharmaceutically acceptable salt thereof, is about 40 mg to about 50 mgtwice daily.

In some embodiments, the effective amount of cerdulatinib, or apharmaceutically acceptable salt thereof, is about 30 mg to about 40 mgtwice daily.

The dose of cerdulatinib administered can range from about 5 mg to about150 mg daily. In some embodiments, cerdulatinib is administered at 45mg, 50 mg, 55 mg, 60 mg, 65 mg or even more. Further, the half-life ofcerdulatinib is enough to afford once-daily dosing. In some aspects, theeffective amount of cerdulatinib is from about 25 mg to about 140 mgdaily, from 25 mg to 120 mg daily, from 30 mg to 110 mg daily, from 40mg to 100 mg daily, from 45 mg to 90 mg daily, from 50 mg to 80 mgdaily. In some aspects, the effective dose is at least 20 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, or 80 mgdaily. In some aspects, the effective dose is not greater than 150 mg,140 mg, 130 mg, 120 mg, 110 mg, 100 mg, or 90 mg daily. In some aspects,the daily dose is about 30 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg,75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140mg, or 150 mg.

In some aspects, cerdulatinib is administered once daily or twice daily.For once daily, the dose can be about 40 mg, 45 mg, 50 mg, 55 mg, 60 mg,65 mg, or 70 mg. For twice daily, each dosing can be about 25 mg, 30 mg,35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 60 mg.

In one embodiment, the cerdulatinib is administered in a composition.The present disclosure provides compositions comprising a cerdulatiniband a pharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are known to one having ordinary skill in the art may be used,including water or saline. As is known in the art, the components aswell as their relative amounts are determined by the intended use andmethod of delivery. The compositions provided in accordance with thepresent disclosure are formulated as a solution for delivery into apatient for treating cancer. Diluent or carriers employed in thecompositions can be selected so that they do not diminish the desiredeffects of the cerdulatinib. Examples of suitable compositions includeaqueous solutions, for example, a solution in isotonic saline, 5%glucose. Other well-known pharmaceutically acceptable liquid carrierssuch as alcohols, glycols, esters and amides, may be employed. Incertain embodiments, the composition further comprises one or moreexcipients, such as, but not limited to ionic strength modifying agents,solubility enhancing agents, sugars such as mannitol or sorbitol, pHbuffering agent, surfactants, stabilizing polymer, preservatives, and/orco-solvents.

In certain embodiments, a polymer matrix or polymeric material isemployed as a pharmaceutically acceptable carrier or support for theanti-adhesion composition. The polymeric material described herein maycomprise natural or unnatural polymers, for example, such as sugars,peptides, protein, laminin, collagen, hyaluronic acid, ionic andnon-ionic water soluble polymers; acrylic acid polymers; hydrophilicpolymers such as polyethylene oxides, polyoxyethylene-polyoxypropylenecopolymers, and polyvinylalcohol; cellulosic polymers and cellulosicpolymer derivatives such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, methyl cellulose, carboxymethyl cellulose, and etherifiedcellulose; poly(lactic acid), poly(glycolic acid), copolymers of lacticand glycolic acids, or other polymeric agents both natural andsynthetic. In certain embodiments, the anti-adhesion compositionsprovided herein is formulated as films, gels, foams, or and other dosageforms.

Suitable ionic strength modifying agents include, for example, glycerin,propylene glycol, mannitol, glucose, dextrose, sorbitol, sodiumchloride, potassium chloride, and other electrolytes.

In certain embodiments, the solubility of the cerdulatinib may need tobe enhanced. In such cases, the solubility may be increased by the useof appropriate formulation techniques, such as the incorporation ofsolubility-enhancing compositions such as mannitol, ethanol, glycerin,polyethylene glycols, propylene glycol, poloxomers, and others known inthe art.

Formulations contemplated by the present disclosure may also be foradministration by injection include aqueous or oil suspensions, oremulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, aswell as elixirs, mannitol, dextrose, or a sterile aqueous solution, andsimilar pharmaceutical vehicles. The cerdulatinib can be administeredsystemically or directly at (or near) a tumor site. In some embodiments,the administration is intra-arterial or intravenous. Suitable means foradministration include needle (including microneedle) injectors,infusion techniques, and catheter-based delivery.

Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present disclosure. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

Sterile injectable solutions are prepared by incorporating the componentin the required amount in the appropriate solvent with various otheringredients as enumerated above, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum-drying and freeze-drying techniques which yield apowder of the active ingredient plus any additional desired ingredientfrom a previously sterile-filtered solution thereof.

In making pharmaceutical compositions that include cerdulatinib, theactive ingredient is usually diluted by an excipient or carrier and/orenclosed within such a carrier that can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of films, gels, patches,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium),ointments containing, for example, up to 10% by weight of the activecompounds, soft and hard gelatin films, gels, patches, sterileinjectable solutions, and sterile packaged powders.

In certain embodiments, the cerdulatinib described herein, or acomposition comprising the same, is lyophilized prior to, during, orafter, formulation. Accordingly, also provided herein is a lyophilizedcomposition comprising a cerdulatinib or composition comprising the sameas described herein.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

EXAMPLES Example 1. Expression and Inhibition of p90RSK in MultipleMyeloma Cell Lines

Six multiple myeloma cell lines were tested in this example for theexpression level of p90RSK. The cell lines included LP1, OPM2, MOLP1,RPMI8226, U266B1, and NCIH929. Beta-actin was used as control, and theexpression levels of FGF receptor 3 (FGFR3), phospho-5380 RSK, andRSK1/RSK2/RSK3 were also measured.

As shown in FIG. 1, p90RSK was positive in all cell lines. Further, theexpression levels of p90RSK (as well as of RSK-5380) were not associatedwith that of FGFR3, which was only detected in two of the cell lines. Asannotated in the figure, three cell lines (LP1, OMP2, and NCIH929) hadt(11;14) FGFR3 activation mutation.

A p90RSK inhibitor, BI-D1870 (see, e.g., Sapkota et al., Biochem J.2007, 401(Pt 1): 29-38), was added to the medium for each cell line atthree difference concentrations, 1.2 μM, 2.5 μM, and 5 μM. As shown inFIG. 2, BI-D1870 dose-dependently activated the expression of Caspase3,an indicator of cell apoptosis. Further, the induction did not correlatewith the FGFR3 status of the cell lines.

In a similar experiment, BI-D1870 dose-dependently inhibited cellproliferation of the cell lines (FIG. 3), which inhibition also did notcorrelate with the FGFR3 status.

Example 2. Cerdulatinib Activated Apoptosis and Inhibited Proliferationof Multiple Myeloma Cell Lines

Cerdulatinib was tested with same cell lines as used in Example 1. Asshown in FIGS. 4 and 5, like BI-D1870, cerdulatinib activated apoptosisand inhibited cell proliferation in these multiple myeloma cell lines.Also like BI-D1870, there was no relationship between the activity ofcerdulatinib and the status of FGFR3.

This example suggests that cerdulatinib can treat multiple myeloma in anFGFR3-independently manner.

Example 3. Cerdulatinib is Potent in Killing Other Cancer Cells

The cytotoxicity of cerdulatinib in AML (Acute Myeloid Leukemia) wastested in four different cell lines. As shown in FIG. 6, cerdulatinibwas more active than Ruxolitinib, a JAK inhibitor, and Comp A(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),a Syk inhibitor. This experiment, therefore, demonstrates cerdulatinib'sability in treating AML.

The cytotoxicity of cerdulatinib was also compared to Comp A in othertypes of cancer cells. As shown in FIG. 7, across DLBCL (Diffuse largeB-cell lymphoma), MCL (Mantle Cell Lymphoma), Burkitt's lymphoma, ALL(Acute Lymphoblastic Leukemia), MM (Multiple Myeloma) and AML cells,cerdulatinib was more potent than Comp A, a potent Syk inhibitor.

Example 4. Drug Exposure and Dosing

Earlier studies had shown that the PK of cerdulatinib makes it suitablefor once daily dosing with a half-life of 12-16 hours and a 2:1peak-trough ratio. The present example, however, demonstrated that BIDdosing could achieve even higher exposures, which was also testedclinically as described below.

Methods:

This experiment was a 3+3 dose escalation study with 28-day cycles anddoses studied ranging from 15 mg to 100 mg QD, and up to 45 mg BID. PK,PD, and safety were monitored. Clinical response was assessed bystandard criteria. The level of inhibition of SYK and JAK was determinedby multiple whole blood assays measuring signaling via BCR, IL4, IL6,and GM-CSF. Serum markers of tumor burden—CCL3, CCL4, and other markersof inflammation—β2M, CRP, were also measured.

Results:

As of Jan. 7, 2016, 41 patients (pt) with CLL/SLL or B cell NHL weredosed. Median age was 67 years (range 23-85) and median prior therapies(tx) was 3 (range 1-8). Treatment emergent AEs of ≥grade 3 observeddeemed related to study drug were: neutropenia (n=2), anemia (n=1), andpneumocystis pneumonia (grade 5, n=1) at 30 mg; anemia, AST increase,hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 foreach) at 50 mg, diarrhea and fatigue (n=1 for each) at 65 mg, nausea(n=1) at 100 mg, and pancreatitis (n=1) at 45 mg BID. The patient withgrade 3 AST had tumor progression to the liver. The pancreatitis at 45mg BID was considered at DLT and the cohort is expanding toapproximately 6 patients.

In general. cerdulatinib was well tolerated. Ten total patients haveremained on cerdulatinib for over 200 days, including two who have beenon for a year or more. Once daily dosing of 40-100 mg resulted in 50 to100% inhibition of SYK and JAK signaling at steady-state C_(min) toC_(max), respectively, in peripheral blood of dosed patients.Significant inhibition of serum markers of inflammation was observed atthese doses, and the extent of inhibition correlated with tumorresponse.

At the 45 mg BID dose level, complete inhibition of SYK and JAK atsteady-state C_(min) in peripheral blood assays was observed, consistentwith an approximate doubling in exposure. Over the 40-100 mg dose range,the average steady state C_(min) and C_(max) concentrations plateaued at0.70±0.20 and 1.38±0.23 respectively. While PK is suitable for oncedaily dosing with a half-life of 12-16 hours and a 2:1 peak-troughratio, the low pH solubility appeared to limit dissolution.

By switching to a 45 mg BID dose, steady-state C_(min) was increased toapproximately 1.5 a concentration sufficient to induce apoptosis inpre-clinical tumor models using both primary cells and cell lines.Partial responses (n=4) were observed at 30 mg in a pt with del 17p CLLwho had relapsed after 6 prior tx; at 45 mg a pt with CLL who hadreceived 4 prior tx, and another pt with FL who had received 3 prior tx;and at 65 mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6expression by IHC) who had relapsed approximately 1 year after 1 priortx. Responses occurred after 2 cycles of tx. Thus far, the extent oftumor response significantly correlated with systemic exposure of drug,which has doubled in the 45 mg BID dose group relative to previous doselevels.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” “containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed.

Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the inventionsembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this invention. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

1. A method of treating multiple myeloma (MM), acute myeloid lymphoma(AML) or a myeloproliferative disease (MPD) in a human patient in needthereof, comprising administering to the patient an effective amount ofcerdulatinib or a pharmaceutically acceptable salt thereof, wherein theeffective amount is from about 5 mg to about 150 mg daily.
 2. The methodof claim 1, wherein the patient is not being treated with fludarabine.3. The method of claim 1, wherein the patient is not being treated witha purine analog.
 4. The method of claim 1, wherein the patient is notbeing treated with an agent that interferes with DNA synthesis.
 5. Themethod of claim 1, wherein the administration is once daily.
 6. Themethod of claim 1, wherein the administration is twice daily.
 7. Themethod of claim 6, wherein the effective amount is from about 25 mg toabout 65 mg twice daily.
 8. The method of claim 6, wherein the effectiveamount is about 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg twice daily.
 9. Themethod of claim 1, wherein the patient suffers from an advancedmalignancy of MM, AML or MPD.
 10. The method of claim 1, wherein thepatient has relapsed or not responded to a prior chemotherapy.
 11. Themethod of claim 10, wherein the patient has failed at least two priortherapies.
 12. The method of claim 1, wherein the multiple myeloma is aStage I, Stage II, or Stage III multiple myeloma.
 13. The method ofclaim 1, wherein the patient has an albumin level lower than 3.5 mg/dL.14. The method of claim 1, wherein the patient has a B2-microglobulinlevel from 3.5 to 5 mg/L or greater than 5 mg/L.
 15. The method of claim1, wherein the patient has an FGFR3 activation mutation.
 16. The methodof claim 1, wherein the multiple myeloma is Monoclonal Gammopathy ofUndetermined Significance (MGUS), Asymptomatic (Smoldering/Indolent)Myeloma, or Symptomatic (Active) Myeloma.
 17. The method of claim 1,further comprising administering to the patient a second agent.
 18. Themethod of claim 17, wherein the second agent is a P90RSK inhibitor. 19.The method of claim 17, wherein the second agent is selected from thegroup consisting of dexamethasone, melphalan, doxorubicin, bortezomib,lenalidomide, prednisone, carmustine, etoposide, cisplatin, vincristine,cyclophosphamide, BI-D1870, and thalidomide.